Acute myeloid leukemia (AML) is a disease characterized by the rapid proliferation of immature myeloid cells in the bone marrow resulting in dysfunctional hematopoiesis [1]. First-line treatments for acute myeloid leukemia (AML) have remained largely unchanged for nearly 50 years and AML remains a disease of poor prognosis. Although standard induction chemotherapy can induce complete remissions, many patients eventually relapse and succumb to the disease [2]. Therefore, the development of novel therapeutics for AML is crucial.
Allogeneic hematopoietic cell transplantation can achieve cure of the disease in selected patients and highlights the susceptibility of AML to donor derived immunotherapy. Additionally, the interleukin 3 receptor alpha chain (CD123) has been identified as a potential immunotherapeutic target since it is over-expressed on AML compared to normal hematopoietic stem cells.
Recent advances in the immunophenotyping of AML cells have revealed several AML associated cell surface antigens that may act as targets for future therapies [3]. Indeed, pre-clinical investigations using antibodies targeting CD44, CD47, T cell immunoglobulin mucin-3 (TIM-3) and the interleukin 3 receptor alpha chain (IL-3Rα; CD123) for the treatment of AML have been described and demonstrated promising anti-leukemic activity in murine models [3, 4]. CD123 is expressed on various malignancies including acute and chronic myeloid leukemia, hairy cell leukemia, B-cell lineage acute lymphoblastic leukemia, and blastic plasmacytoid dendritic cell neoplasms. Additionally, CD123 is not typically expressed on normal hematopoietic stem cells, thus making CD123 an ideal immunotherapeutic target. Additionally, two phase I trials for CD123-specific therapeutics have been completed with both drugs displaying good safety profiles (ClinicalTrials.gov ID: NCT00401739 and NCT00397579). Unfortunately, these CD123 targeting drugs had limited efficacy suggesting that alternative, and more potent therapies targeting CD123 may be required to observe anti-leukemic activity.
A possibly more potent alternative therapy for the treatment of AML is the use of T cells expressing chimeric antigen receptors (CARs) that redirect T cell specificity towards cell surface tumor associated antigens (TAAs) in an MHC-independent manner [5]. In most cases, CARs include a single-chain variable fragment (scFv) from a monoclonal antibody fused to the signaling domain of CD3ζ and may contain a costimulatory endodomain [5]. Several groups have developed CARs targeting various antigens for the treatment of B-cell malignancies [6-10] and many have gone on to evaluating CAR expressing T cells in phase I clinical trials [11-15]. In contrast, CAR engineered T cells for the treatment of AML remain scarce [16, 17].
Although current treatment regimes for AML can achieve complete responses in select patients, many will eventually relapse underscoring the need for novel therapeutics which may lead to more durable responses. Various AML targeting immunotherapies including antigen specific cytotoxic T lymphocytes, alloreactive natural killer cells, and dendritic cell vaccines are currently being developed. For example, Oka and colleagues have demonstrated that Wilms' Tumor 1 peptide vaccination can lead to clinical and immunological responses in AML patients [33]. However, these targeting therapies are HLA-dependent. To this end, it would be desirable to design a targeted therapeutic, such as a CAR, that can redirect T cell specificity to selectively target AML cells in an HLA-independent manner.